title: Characterization of the stereochemical structures of 2H-thiazolo[3,2-a]pyrimidine compounds and their binding affinities for anti-apoptotic Bcl-2 family proteins.
abstract: In a previous study we reported a class of compounds with a 2H-thiazolo[3,2-a]pyrimidine core structure as general inhibitors of anti-apoptotic Bcl-2 family proteins. However, the absolute stereochemical configuration of one carbon atom on the core structure remained unsolved, and its potential impact on the binding affinities of compounds in this class was unknown. In this study, we obtained pure R and S enantiomers of four selected compounds by HPLC separation and chiral synthesis. The absolute configurations of these enantiomers were determined by comparing their circular dichroism spectra to that of an appropriate reference compound. In addition, a crystal structure of one selected compound revealed the exocyclic double bond in these compounds to be in the Z configuration. The binding affinities of all four pairs of enantiomers to Bcl-xL , Bcl-2, and Mcl-1 proteins were measured in a fluorescence-polarization-based binding assay, yielding inhibition constants (Ki values) ranging from 0.24 to 2.20 μM. Interestingly, our results indicate that most R and S enantiomers exhibit similar binding affinities for the three tested proteins. A binding mode for this compound class was derived by molecular docking and molecular dynamics simulations to provide a reasonable interpretation of this observation.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P.R. China.
authors.forename: Yaochun
authors.initials: Y
authors.lastname: Xu
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Chengke
authors.initials: C
authors.lastname: Li
authors.forename: Zhengxi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Biao
authors.initials: B
authors.lastname: Yu
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D007700:Kinetics; D008968:Molecular Conformation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D051020:bcl-X Protein; C039201:thiazolo(3,2-a)perimidine
keywords: Bcl-2; binding affinity; chirality; inhibitors; protein-protein interactions; small molecules